Chemists have finally found a way to functionalize one of the most common and most inert of organic chemical bonds, the carbon-hydrogen bond. The result is the culmination of more than a quarter of a century of effort. The work will open up a new repertoire of synthetic schemes. [Oeschger, R. et al., Science (2020); 368 (6492): 736 DOI: 10.1126/science.aba6146]
"Carbon-hydrogen bonds are usually part of the framework, the inert part of a molecule," explains John Hartwig of the University of California Berkeley. "It has been a challenge to be able to do reactions at these positions because, until now, there has been no reagent or catalyst that will allow you to add anything at the strongest of these bonds."
There have been many advances in C-H bond chemistry but Hartwig and his colleagues have developed a catalyst that can crack even the toughest carbon-hydrogen bonds, the ones that are usually at the head or the tail of a molecule in a methyl group.
"The primary C-H bonds, the ones on a methyl group at the end of a chain, are the least electron-rich and the strongest," he explains. "They tend to be the least reactive of the C-H bonds."
Hartwig's post-doc researcher Raphael Oeschger discovered a new version of a catalyst based on iridium that can open a terminal methyl group and insert a borane. This grouping is much more reactive and can be swapped out for other complex chemical groups. The catalyst is more than fifty times as efficient as any earlier catalyst. They were able to do swap in the borane in 63 test compounds and then functionalize the original structure through this intermediate.
"We now have the ability to do these types of reactions, which should enable people to rapidly make molecules that they would not have made before," Hartwig adds. "I wouldn't say these are molecules that could not have been made before, but people wouldn't make them because it would take too long, too much time and research effort, to make them."
"Classically, you can make a carbon-oxygen bond from that, but you can also make a carbon-nitrogen bond, a carbon-carbon bond, a carbon-fluorine bond or other carbon-halogen bonds," adds Hartwig. "So, once you make that carbon-boron bond, there are many different compounds that can be made."
Hartwig explains that this is a first step, yields are between 29 and 85 percent in the final product, but improvements on reaction conditions and reagents will push this higher eventually.